Pregnancy-induced hypertension (PIH) is estimated to affect 5-10% of all pregnancies in the United States and is a leading cause of maternal death and perinatal morbidity and mortality. Despite the large number of pregnancies affected, the mechanisms underlying the pathogenesis of PIH remain unclear. Recent evidence from clinical studies indicates that a soluble form of the vascular endothelial growth factor (VEGF) receptor (sFlt-1) is elevated in the placenta and plasma of women with PIH. Moreover, adenovirus mediated administration of sFlt-1 to pregnant rats to mimic plasma concentrations observed in pre-eclamptic women, decreases free VEGF and PIGF and produces hypertension. Presently, the mechanisms that underlie the origins of excess placenta! and plasma sFlt-1 as well as the mechanisms by which sFlt-1 mediates PIH are unknown. Thus, the central hypothesis to be tested in this proposal is reductions in uterine perfusion pressure in pregnant rats increase plasma concentration of sFlt-1 and decreased plasma concentrations of VEGF and PIGF. In-addition, we propose that sFIt increases blood pressure by decreasing plasma concentrations of free VEGF and PLGF which, in turn, causes endothelial cell dysfunction marked by enhanced production of ET-1, ROS and decreased NO. To test this hypothesis arterial pressure (AP), renal, hormonal, and endothelial factors will be examined in a conscious, chronically instrumented rat model of chronic PIH produced by long-term reductions in uterine perfusion pressure (RUPP). In addition to the RUPP model, a sFlt-1 model of PIH will be used to determine the interaction between sFlt-1 and ET-1, ROS, and NO production while an in vitro placental explant model will be used to examine the direct interaction between hypoxia, cytokines, and placental sFlt-1 production. Specific aims are: 1) To test the hypothesis that reduced uterine perfusion in pregnant rats increases plasma concentrations and placental levels of sFlt-1 and decreases plasma concentrations of VEGF and PIGF. 2) To test the hypotheses that enhanced formation of ET-1 and decreased levels of NO mediate the reduction in renal function and elevation in AP that occurs during sFlt-1 infusion induced hypertension in pregnant rats. 3) To test the hypothesis that enhanced formation of ROS mediates the reduction in renal function and elevation in AP that occurs during sFlt-1 infusion induced hypertension in pregnant rats. RELEVANCE: The results of these experiments will provide new information regarding the cause of increased sFlt-1 during PIH and describe the manner in which sFlt-1 mediates the reductions in renal and cardiovascular function during PIH. The increased understanding of the function of sFlt-1 in PIH may lead to novel therapies for the treatment of PIH. [unreadable] [unreadable] [unreadable] [unreadable]